The bromodomain (BRD) family of proteins recognizes and binds to the acetylated lysine acting as a reader of lysine acetylation state. These “epigenetic readers” bind to acetyllysine residues on the tails of histones H3 and H4, and regulate chromatin structure and gene expression. There is increasing evidence of their role in human disease, and recently a number of small-molecule nihibitors have been reported. There is increasing evidence for the roles of BRDs in disease including inflammation, neurological indications, viral infection, cancers, and autoimmune disorder.
An analysis of the human proteome has revealed that there are eight distinct BRD families, representing 61 different BRDs from 46 separate proteins, although others may still be undiscovered. The BET family of BRDs is a subset of this larger bromodomain family and is made up of four members: BRD2, BRD3, BRD4, and BRDT in humans. BRD2 and BRD3 are reported to associate with histones along activity transcribed genes and may be involved in facilitating transcriptional elongation, while BRD4 appears to be involved in the recruitment of the P-TEFb complex to inducible genes, resulting in phosphorylation of RNApolymerase and increased transcription output. Chromosomal translocation of BRD3 and BRD4 to the nuclear protein in testis (NUT) locus generates BRD3-NUT or BRD4-NUT fusion protein that results in c-Myc overexpression and NUT midline carcinoma (NMC), an aggressive squamous cell malignancy unresponsive to conventional chemotherapeutics. BRDT is uniquely expressed in the testes and ovary.
Recently, a number of small-molecule compounds with potent inhibitory activity against BET family proteins have been reported. The first potent BET inhibitor was the diazepine JQ1 by nuclear magnetic resonance technology, subsequently, more molecues were reported by epigenetic screening and targeted biochemistry. By these potent inhibitors, more knowledge about the relationship of BET proteins and diseases was disclosed. Rapid progress in the development of bromodomain ligands has stimulated extensive interest and has led to several BET bromodomain inhibitors reaching clinical trials for cancers and inflammations.